1. Technical Field
The present invention relates to the use of losartan in a gastric retained dosage form. More specifically, the invention relates to the use of such dosage form to treat hypertension and other disease states.
2. Background
Losartan was the first orally active angiotensin II receptor antagonist (McIntyre, et al., Pharmacol. Ther. 74(2):181-194 (1997); Siegel, Journal of Hypertension 11(3):S19-S 22(1993)). At present, losartan is marketed as losartan potassium (C22H22ClKN6O), which is chemically described as 2-butyl-4-chloro-1[p-(o-1H-tetrazol-5-ylphenyl) benzyl]imidazole-5-methanol monopotassium salt. Losartan potassium is administered to treat hypertension and is commercially available in 25 mg, 50 mg and 100 mg tablet dosage forms. Dosage regimens are typically 25 mg to 100 mg either once- or twice-daily.
The effects of losartan potassium are observed at 24 hours for both the 50 mg and the 100 mg dosages, but not for the 25 mg dosage (McIntyre, et al., supra). McIntyre also observes that there is an approximately 30% blockade of the diastolic pressure response to angiotensin II at 24 hours after dosing. Further, the peak:trough blood pressure ratio (5-6 hours after dosing: 24 hours after dosing) was found to be 60% for a 50 mg dosage and 72% for a 100 mg dosage.
Although some researchers have noted that once-daily and twice-daily administrations demonstrate equivalent efficacy, Bauer, et al., Arch. Intern. Med. 155:1361-1368 (1995) has indicated that a 50 mg twice daily dosing regimen is more effective than a 100 mg once-daily dosing regimen. Since the blood pressure responses tends to closely follow the plasma levels of the active metabolite of losartan potassium, and the tmax and half-life of the active metabolite are 2-4 hours and 6-9 hours (4-5 for Japanese patients tested), respectively (Bauer, et al., supra), the superiority of the bid dosing is expected.
A controlled release formulation of losartan would have the desirable benefit of eliminating the need for bid dosing. It was hypothesized that a gastric retentive controlled release dosage form may improve the absorption of losartan.
These problems are addressed by the instant invention, which provides for the once-daily delivery of losartan by means of a gastric retained dosage form to treat hypertension. A gastric retained dosage form is particularly beneficial for delivery of losartan due to its prolonged transit in the upper gastrointestinal tract and thus not have the problem of reduced bioavailability.